Bronchial airway deposition and retention of particles in inhaled boluses: effect of anatomic dead space

The fractional deposition of particles in boluses delivered to shallow lung depths and their subsequent retention in the airways may depend on the relative volume and size of an individual's airways. To evaluate the effect of variable anatomic dead space (ADS) on aerosol bolus delivery we had healthy subjects inhale radiolabeled, monodisperse aerosol (99mTc-iron oxide, 3.5 micron mean mondispersed aerosol diameter) boluses (40 ml) to a volumetric front depth of 70 ml into the lung at a lung volume of 70% total lung capacity end inhalation. By using filter techniques, aerosol photometry, and gamma camera analysis, we estimated the fraction of the inhaled boluses deposited in intrathoracic airways (IDF). ADS by single-breath N2 washout was also measured from 70% total lung capacity. Results showed that among all subjects IDF was variable (range = 0.04-0.43, coefficient of variation = 0.54) and increased with decreasing ADS (r = -0.76, P = 0.001, n = 16). We found significantly greater deposition in the left (L) vs. right (R) lungs; mean L/R (ratio of deposition in L lung to R lung, normalized to ratio of L-to-R lung volume) was 1.58 +/- 0.42 (SD; P < 0.001 for comparison with 1.0). Retention of deposited particles at 2 h was independent of ADS or IDF. There was significant retention of particles at 24 h postdeposition (0.27 +/- 0.05) and slow clearance of these particles continued through 48 h postdeposition. Finally, analysis of central-to-peripheral ratios of initial deposition and 24-h-retention gamma-camera images suggest significant retention of insoluble particles in large bronchial airways at 24 h postdeposition (i.e., 24 h central-to-peripheral ratio = 1.40 +/- 0. 44 and 1.82 +/- 0.54 in the R and L lung, respectively; P < 0.02 for comparison with 1.0). These data may prove useful for 1) designing aerosol delivery techniques to target bronchial airways and 2) understanding airway retention of inhaled particles.     

Cellular mechanisms of adrenaline-stimulated anion secretion by the mouse endometrial epithelium

As freon is limited in its use as a generator for aerosol inhalation, powder particles are used as an alternative for inhalation therapy. The pulmonary deposition and clearance of inhaled powder particles was studied by positron emission tomography (PET) in ten patients with chronic obstructive pulmonary disease (COPD) and in five normal controls. The powder, 5 microm in mean diameter, was water soluble and labelled with 2-deoxy-2-[18F]-fluoro-D-glucose (18FDG). Powder inhalation was done with single deep inspiration from residual volume to total lung capacity. The initial deposition ratio in the right or left lung field to total inhaled dose, measured by an anteroposterior rectilinear scan, did not differ between normals and COPD patients. Ratios of radioactivity detected within the central and peripheral regions (the central to peripheral ratio) measured by the PET scan was not significantly different between COPD patients (4.8+/-2.6, mean+/-SD) and normals (2.6+/-0.8, mean+/-SD). However, the regional powder deposition in peripheral lung fields measured by the PET scan was significantly more uneven in COPD patients than in normal patients. The clearance rate of 18FDG, defined as the retention ratio of 18FDG activity to the initially deposited 18FDG at 60 and 120 min after inhalation, in the trachea, large bronchi or peripheral lung fields measured by tomographic scan showed a wider variation in COPD patients than in normals. To conclude, inhaled powder tended to be deposited more centrally and was distributed more unevenly in the peripheral lung in chronic obstructive pulmonary disease patients than in normals. This could be a limitation of powder inhalation used for therapy in chronic obstructive pulmonary disease patients.     

Clinical and endoscopic predictors of histological oesophagitis in infants

Therapeutic aerosols pay an increasing role in the treatment of equine respiratory disorders. This route of delivery permits concentration of significant amounts of drugs at the site of action without unwanted high systemic concentration and resultant side effects. The efficiency of such a topical therapy depends on the quantity of inhaled drugs deposited in the lungs and, for some drugs, on the proportion retained in specific parts of the lungs. The objective of this study was to define and to compare quantitative (dose deposited) and qualitative (regional distribution) deposition of an aerosol in the equine lungs, using either a ultrasonic nebuliser (UN) currently used in human medicine or a high pressure jet nebuliser (JN) especially developed for the equine species. This comparison was possible owing to gamma-scintigraphy, a noninvasive technique ideally suited to give information about both total and regional deposition of inhaled drugs in the respiratory tract. The quantitative study did not point out any difference between the 2 systems concerning the activity released from the nebuliser proportionally to the initial loaded dose (mean +/- s.d. 45.95 +/- 4.93% for the UN vs. 46.47 +/- 8.49% for the JN). By contrast, the percentage of the dose released reaching the lungs was significantly lower with the UN compared to the JN (5.09 +/- 0.66% vs. 7.35 +/- 1.96%). The qualitative analysis did not show any significant difference in size of aerosol deposition image between the 2 nebulisers. However peripheral deposition was significantly higher with JN compared to UN. In conclusion, both nebulisers may be used for aerosol therapy in the equine species. The ultrasonic and pneumatic nebulisation achieved drug deposition in the peripheral part of the lungs (i.e. small airways and lung parenchyma).     

Inhalation of dry-powder mannitol increases mucociliary clearance

Inhalation of hypertonic saline stimulates mucociliary clearance (MCC) in healthy subjects and those with obstructive lung disease. We investigated the effect of inhaling the osmotic agent mannitol on MCC. We used a dry-powder preparation of mannitol British Pharmacopea (BP) which was encapsulated and delivered using a Dinkihaler. MCC was measured for 75 min in six asthmatic and six healthy subjects on two occasions before and after the mannitol inhalation or its control, using 99mTc-sulphur colloid and a gamma camera. The inhaled dose of mannitol was 267+/-171 mg (mean+/-SD) and 400 mg and the percentage fall in forced expiratory volume in one second (FEV1) was 22+/-3 and 4+/-2% in the asthmatic and healthy subjects, respectively. The total clearance in the whole right lung for the 60 min from the start of inhalation of mannitol was greater by 263+/-11.9% in the asthmatic and 18.1+/-4.9% in the healthy subjects compared to the control. The total clearance over 75 min was 54.7+/-9.6% and 33.6+/-9.4% on the mannitol and control day (p<0.002), respectively, in the asthmatic subjects and 40.5+/-7.1% and 24.8+/-7.8% (p<0.002) in the healthy subjects. In conclusion, inhalation of dry-powder mannitol increases mucociliary clearance in asthmatic and healthy subjects and may benefit patients with abnormal mucociliary clearance.     

Inhalation therapy in children younger than 2 years. II. The practice

Effective inhalation of drugs, even by small children under 2 years, is often faster, simpler, cheaper and better with metered dose inhalers with small antistatic (metal) inhalation chambers than with nebulisation. This is also true during considerable bronchial obstruction. It is mandatory that the inhalation chamber has a small dead space and well functioning valves opening at low flows. Effective dosing in small children is enhanced by more doses, given separately, while choosing the highest dose per spray available. Important factors determining bronchial deposition in small children are breathing frequency, tidal volume and the degree of bronchial obstruction and nasal obstruction, since inhalation goes primarily through the nose. If well-performed medication with a small inhalation chamber is clinically ineffective, it is better to start systemic medication, e.g. a corticosteroid, or even to consider artificial ventilation, rather than to try nebulisation. Better effective deposition is possible with inhalation of drugs in hydrofluoroalkane (HFA) aerosols, which will replace chlorofluorocarbon (CFC) aerosols in the near future.     

Postoperative analgesia with intramuscular morphine at fixed rate versus epidural morphine or sufentanil and bupivacaine in patients undergoing major abdominal surgery

Hydrofluoroalkane-134a (HFA) beclomethasone dipropionate (BDP) was formulated in a metered-dose inhaler (MDI) to deliver a particle size of 1.1 microm compared with 35 microns for currently marketed chlorofluorocarbon (CFC)-BDP products. Two phase I single-dose human deposition studies were conducted using technetium 99m-radiolabelled BDP in a press-and-breathe actuator without an add-on spacer. A healthy volunteer study (n=6) showed that 55-60% of the HFA-BDP ex-actuator dose was deposited in the lungs, with 29-30% deposited in the oropharynx. CFC-BDP deposition was 4-7% in the lungs and 90-94% in the oropharynx. The pattern of deposition within the lung showed that HFA-BDP was spread diffusely throughout the lung airways, whereas CFC-BDP was confined to the central airways with little, if any, peripheral airway deposition. A second study with asthmatics (n=16) confirmed that 56% of the HFA-BDP dose was deposited in the airways, with 33% in the oropharynx. In conclusion, hydrofluoroalkane-134a-beclomethasone dipropionate deposition was much greater in the airways than chlorofluorocarbon-beclomethasone dipropionate, with a concomitant reduction in oropharyngeal deposition. The increased lung deposition efficiency of the hydrofluoroalkane propellant has led to a reduction in the amount of beclomethasone dipropionate needed to achieve a similar efficacy. The penetration of the hydrofluoroalkane to the small airways may provide asthma treatment not afforded by conventional chlorofluorocarbons.     

Isolation and characterization of mitochondria from turkey spermatozoa

The purpose of the present investigation was to evaluate 99Tcm-labelled alpha-D-glucose 1-phosphate (GP) aerosols for single photon emission computed tomographic (SPECT) ventilation lung imaging in comparison to 99Tcm-diethylenetriaminepentaacetate (DTPA) aerosols. Ten normal nonsmoking male volunteers (aged 20-30 years) were included in this study after obtaining their informed consent. 99Tcm-GP, 30 mCi, in 2 ml was placed in the nebulizer (Venticis II) and inhalation continued for 5 min of normal breathing with oxygen flowing through. In 10 subjects dynamic images were obtained from the posterior position for 90 min with 45 frames on a 64 x 64 matrix by the use of a gamma camera. At the end of the dynamic study planar images of the lung (anterior, posterior and laterals) were recorded. Decay corrected clearance curves and kep values were obtained by the pulmonary epithelial programme and T1/2 values were calculated. The same procedure was followed by the use of 99Tcm-DTPA in the same subjects 2 weeks later. SPECT studies of the lung were performed in five subjects after inhalation of 99Tcm-GP aerosols. Clearance curves were monoexponential. The difference in T1/2 values between the right and left lungs was statistically insignificant (P > 0.10). The mean T1/2 values were 316.5 +/- 44.7 and 80.8 +/- 13.4 min for 99Tcm-GP and 99Tcm-DTPA, respectively. The difference was significant (P < 0.0005). On scintigraphic images 99Tcm-GP showed high alveolar deposition and low adhesion to major airways like 99Tcm-DTPA. However, it is preferred to 99Tcm-DTPA for SPECT studies because of its prolonged pulmonary clearance.     

Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices

STUDY OBJECTIVES: To compare lung deposition of fenoterol or flunisolide administered from a novel, multidose inhalation device delivering liquid droplets (RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered-dose inhalers (MDIs) with and without spacers. DESIGN: Two randomized, three-way crossover studies. SETTING: Clinical research laboratory. PARTICIPANTS: Healthy, nonsmoking volunteers. INTERVENTIONS: In one study, radiolabeled aerosols of fenoterol from the RESPIMAT device and from a conventional MDI with or without an Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim, Germany). MEASUREMENTS AND RESULTS: Assessment of the deposition of fenoterol or flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was assessed based on reported adverse effects and spirometry (FEV1, FVC, and peak expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT device delivered significantly more fenoterol to the lungs than either an MDI alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose, respectively; p<0.01). Oropharyngeal deposition of fenoterol from the new device was lower than that from the MDI (37.1% vs 71.7%, respectively; p<0.01). The RESPIMAT device deposited significantly more flunisolide in the lungs compared with MDI plus spacer (44.6% vs 26.4%, respectively; p<0.01), while resulting in similar oropharyngeal deposition (26.2% vs 31.2%, respectively). Introduction of a baffle into the RESPIMAT system reduced lung deposition of flunisolide to 29.5%, and oropharyngeal deposition to 7.8% (p<0.01). CONCLUSION: The RESPIMAT device may prove to be an effective alternative to MDIs for the administration of inhaled bronchodilators and corticosteroids. The high lung deposition and low oropharyngeal deposition may lead to improved efficacy and tolerability of inhaled medications, especially corticosteroids.     

Metaproterenol responsiveness after methacholine- and histamine-induced bronchoconstriction

We investigated whether the bronchodilator response to a beta-adrenergic agonist is influenced by the mechanism of induced bronchoconstriction. Normal subjects and asymptomatic asthmatics inhaled a dry aerosol (mass median aerodynamic diameter, 1.5 microns) with increasing concentrations of methacholine or histamine to produce a 35% decrease in specific airway conductance (SGaw), followed by a single inhalation of a metaproterenol aerosol. By studying normal subjects and asthmatics, we were able to compare metaproterenol responsiveness after widely divergent doses of the bronchoprovocative agents but the same degree of bronchoconstriction. Airway deposition of methacholine, histamine, and metaproterenol was measured using a quinine fluorescence technique. Mean baseline SGaw, metaproterenol responsiveness, and metaproterenol mass deposited were similar in normal subjects and asthmatics. Likewise, mean SGaw after completion of methacholine and histamine challenge, and the subsequently deposited metaproterenol mass were similar in the two groups. After methacholine challenge (mean +/- SD provocative drug mass causing a 35% decrease in SGaw, PM35: 8.94 +/- 5.96 mumol in normal subject and 0.30 +/- 0.29 mumol in asthmatics), metaproterenol increased mean SGaw by 89 +/- 33% in normal subjects and by 190 +/- 55% in asthmatics (p < 0.05, two-way analysis of variance). After histamine challenge (PM35, 2.92 +/- 2.49 mumol in normal subjects and 0.17 +/- 0.29 mumol in asthmatics), metaproterenol increased mean SGaw by 111 +/- 38% in normal subjects and 113 +/- 69% in asthmatics (p = not significant). Thus, for the same degree of bronchoconstriction, metaproterenol responsiveness was influenced by the dose of methacholine but not the dose of histamine. The differential metaproterenol response could be related to a functional antagonism between muscarinic and beta-adrenergic agonists.     

In vitro performance of three combinations of spacers and pressurized metered dose inhalers for treatment in children

The performance of pressurized metered dose inhalers (pMDIs) and spacers in correct dose recommendations is important, but limited information on dose delivery and fine-particle dose from different combinations of spacers and pMDIs is available. In this study, three combinations of spacers and pMDIs were investigated: NebuChamber and AeroChamber with budesonide pMDI and Babyhaler with fluticasone propionate pMDI. Doses were withdrawn onto a filter either with a breathing simulator (dose to ventilator) or with constant flow (maximal dose). The fine-particle dose was assessed with a cascade impactor (Andersen Sampler). The effect of repeated use and cleaning of the spacers on the passive fallout of aerosol within the spacers was determined by evacuating the dose on a filter 2, 5, 10 and 30 s after actuating the spray. The drugs were quantified by liquid chromatography. The NebuChamber delivered the highest doses, both maximal dose and dose to ventilator. The recovered doses (means+/-SD) were 55+/-6% and 51+/-2%, respectively, of the delivered dose from the pMDI. The corresponding results for the Babyhaler were 41+/-7% and 24+/-4% and for the Aerochamber 27+/-3% and 17+/-3%. The passive fallout of aerosol, determined as half-life (t1/2) was around approximately 30 s for the NebuChamber, 9-15 s for the Babyhaler and approximately 10 s for the AeroChamber. The present study confirms that there are significant differences in dose output from different combinations of pressurized metered dose inhalers and spacers, with the NebuChamber giving the highest dose, both as delivered dose and in droplets <4.7 microm. Interactions with the spacer material, dead space in the inspiratory line and entrainment of air during inhalation due to inefficient valve control could account for these differences.     

Estimating the cost of lost productivity in dyspepsia

In a two-day, randomised, double-blind, double-dummy, cross-over multicenter study, the bronchodilating effect of 100 micrograms of salbutamol (CAS 18559-94-9) inhaled from a new metered dose powder inhaler (MDPI; Taifun) was compared with that of an identical dose of salbutamol inhaled from a conventional pressurised metered dose inhaler connected to a spacer (pMDI + S). Thirty-six non-smoking, adult asthmatic outpatients with a baseline forced expiratory volume in 1 s (FEV1) between 35 and 70% of the predicted value participated in the study. After inhalation of the study medication pulmonary function, FEV1 and airway resistance (R(aw)), blood pressure (BP), and heart rate (HR) were measured up to 6 h. Area under the FEV1 vs. time curve (AUCFEV1) was used as the primary efficacy parameter, and the 90% confidence intervals (CI) were used to judge clinical equivalence. Other efficacy parameters were used in supportive analyses as secondary parameters. Both treatments produced a clear improvement in pulmonary function. The mean +/- SD AUCFEV1 were 893 +/- 281 and 889 +/- 2761.min after MDPI and pMDI + S, respectively. The 90% CI for the relative efficacy of the MDPI is from 98 to 103% of that of the pMDI + S. Also the other efficacy parameters gave similar results without significant differences: the mean +/- SD values of percent increase in FEV1 were 47.2 +/- 19.3 and 44.7 +/- 20.8, the maximum absolute value of FEV1 were 2.87 +/- 0.77 and 2.86 +/- 0.77, the maximum percent decrease in R(aw) 53.2 +/- 20.5 and 55.0 +/- 19.1, and the minimum absolute value of R(aw) 0.27 +/- 0.11 and 0.30 +/- 0.12 kPa.s.l-1 for the MDPI and pMDI + S, respectively. The salbutamol doses had no significant effect on BP or HR, and were equally well tolerated. Furthermore, 57.5% of the patients preferred the MDPI, 35% the pMDI + S, and 7.5% considered that there was no difference between the devices. In conclusion, this study demonstrates that the new MDPI is as effective and safe a device as a conventional pMDI connected to a spacer in administering inhaled salbutamol for asthmatic patients. Further, most patients considered the MDPI easier to handle, and preferred it over the pMDI + S.     

Evaluation of acoustic rhinometry and posterior rhinomanometry as tools for inhalation challenge studies

Objective measures of upper respiratory function are needed to understand the effects of inhaled toxicants on the nasal passages. Acoustic rhinometry (AR) is a simple new technique that determines nasal volume by measuring the cross-sectional area of the upper airway as a function of the distance along the nasal passage. This study compares acoustic rhinometry with the more traditional posterior rhinomanometry (NAR) and correlates these objective measures with the symptom of nasal congestion. Healthy young adults (n = 29) were studied on 4 days, each separated by at least 1 wk, in a climate-controlled environmental chamber for 6 h, with exposure to clean air or sidestream tobacco smoke (SS) (2 h, 1, 5, and 15 ppm CO). The coefficient of variation for single measurements was 8-15% (AR) and 4% (NAR); for across-day measurements it was 15-25% (AR) and 13-15% (NAR); and for between days it was 19-27% AR and 17-21% (NAR). These coefficients were similar in subjects with a history of environmental tobacco smoke sensitivity (ETS-S) and those with no history of ETS sensitivity (ETS-NS). At baseline, the perception of unilateral nasal congestion was significantly correlated with unilateral nasal dimensions or nasal resistance; the symptom of baseline bilateral nasal congestion (estimated for both nasal passages simultaneously) correlated less well with objective measures of nasal patency. Under challenge conditions (SS at 1-15 ppm CO), there were typically significant correlations between changes in unilateral congestion and both unilateral rhinomanometry and acoustic rhinometry, but correlations of bilateral congestion and measurable dimensions were much lower. ETS-S and ETS-NS subjects differed in correlations between bilateral subjective and objective measures: ETS-S subjects showed significant correlation between baseline congestion and NAR; in contrast, ETS-NS subjects showed significant correlation between baseline congestion and acoustic rhinometry. These results indicate that NAR and AR are complementary tests for use in inhalation challenge studies and have different correlations with nasal congestion under baseline and challenge conditions.     

Aerosol therapy

Aerosol therapy plays a major role in the diagnosis and treatment of various lung diseases. The aim of inhalation therapy is to deposit a reproducible and adequate dose of a specific drug to the airways, in order to achieve a high, local, clinical effect while avoiding serious systemic side effects. To achieve this goal, it is therefore important to have an efficient inhalation device to deliver different medications. However, the currently available therapeutic inhalation devices (nebuliser, pressurised metered-dose inhaler and dry powder inhaler) are not very efficient in aerosol delivery and have several disadvantages. Inhalation devices can be assessed by in vitro studies, filter studies and radiolabelled deposition studies. Several radiolabelled deposition studies have shown that nebulisers and pressurised metered-dose inhalers are not very efficient in aerosol delivery. In children, before 1997, only 0.5% to 15% of the total nebulised or actuated dose from a nebuliser or pressurised metered-dose inhaler actually reached the lungs. These numbers were somewhat improved in adults, 30% of the total nebulised or actuated dose reaching the airways. Aerosol therapy with dry powder inhalers was the most efficient before 1997, 30% of the total dose being deposited in the lungs of adults and children. In 1997, new developments in pressurised metered-dose inhalers much improved their efficiency in aerosol delivery. Lung deposition can be increased by up to 60% with use of a non-electrostatic holding chamber and/or a pressurised metered-dose inhaler with a hydrofluoroalkane propellant possessing superior aerosol characteristics. Several studies comparing the clinical efficiency of different inhalation devices have shown that the choice of an optimal inhalation device is crucial. In addition to the aerosol characteristics, ventilation parameters and airway morphology have an important bearing on deposition patterns. These parameters may be greatly influenced by the patient's acceptance of a specific inhalation device and therefore determine the choice of the device used. It is important for the clinical impact to develop more efficient inhalation devices, which need to be assessed for use in different age groups. These devices should be cheap, easy to use, portable, usable with all medications and environmentally safe.     

The analgesic effect of fentanyl, morphine, meperidine, and lidocaine in the peripheral veins: a comparative study

It has been reported that in patients with inflammatory bowel disease (IBD), the airways are involved, and a number of clinical manifestations have been described. The aim of this study was to investigate the function of the small airways in IBD. Thirty patients with IBD (mean age, 47 yr), 12 with Crohn's disease and 18 with ulcerative colitis, were studied and compared with a control group of 16 normal subjects. Maximal expiratory flow-volume curves were performed breathing room air and a mixture of 80% helium, 20% oxygen. The differences of flows at 50% of FVC (delta Vmax50) and the volume of equal flows (Visov) were calculated as indices of small airways function. In addition, spirometry, lung volumes, and diffusing capacity were measured. Visov was statistically significantly greater in patients with either CD or UC than in control subjects (x +/- SD) (24.99 +/- 1.35 and 25.95 +/- 1.5 versus 20.1 +/- 1.39), (p < 0.01 and p < 0.001, respectively). A reduction in TL(CO) was noticed in the active stage of the disease in both groups of patients (p < 0.05). This may indicate that lung parenchyma is also involved in active IBD. Our results suggest that the function of the small airways and diffusion capacity of the lungs are affected in patients with IBD.     

Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios

OBJECTIVE: We determined whether inhaled nitric oxide (NO) could improve systemic oxygenation in human neonates with hypoplastic lungs. METHODS: A multicenter nonrandomized investigation was performed to study the efficacy of short-term NO inhalation. Inhaled NO was administered at 80 ppm to nine neonates without evidence of structural cardiac disease by echocardiography. Lung hypoplasia was due to congenital diaphragmatic hernia (CDH) in eight patients and to oligohydramnios in one patient. A total of 15 trials of NO inhalation were performed in these nine patients. Eight trials in seven patients were performed before extracorporeal membrane oxygenation ((ECMO); one patient had two trials) and seven trials were performed in five patients after decannulation from ECMO (two patients had two trials each). RESULTS: NO inhalation before ECMO did not change postductal PaO2 (42 +/- 3 mmHg vs 42 +/- 4 mmHg), oxygen saturation (SpO2; 89% vs 88%) or oxygenation index (31 +/- 4 cm H2O/torr vs 31 +/- 4 cm H2O/torr) for the group. All patients required ECMO support, which lasted from 5 to 17 days (mean 9). After decannulation from ECMO, NO inhalation increased postductal PaO2 from a median of 56 mm Hg (range 41 to 94) to a median of 113 mm Hg (range 77 to 326), P < .05. It decreased the oxygenation index from a median of 23 cm H2O/torr (range 11 to 7) to a median of 11 cm H2O/torr (range 4 to 21), P < .05. It increased SpO2 from 91% to 96% (P < .05) and pH from 7.48 +/- .03 to 7.50 +/- .03. CONCLUSION: In our patients with hypoplastic lungs, inhaled NO was effective only after ECMO. This could be due to maturational changes such as activating the endogenous surfactant system. Inhaled NO may be effective in neonates with hypoplastic lungs who have recurrent episodes of pulmonary hypertension after ECMO, even if they were previously unresponsive.     

Biodistribution of radiolabeled lipid-DNA complexes and DNA in mice

The tissue biodistribution and expression of [33P]DNA-1-[2-[9-(Z)-octadecenoyloxy]ethyl]]-2-[8](Z)-heptadece nyl]-3 -[hydroxyethyl]imidazolinium chloride (DOTIM):cholesterol complexes and 33P-radiolabeled DNA expressing chloramphenicol acetyl transferase (CAT; 4.7 kB) were studied after intravenous (iv) injection in ICR mice. Mice were injected with 200 microL of complex containing DNA at 3 mg/kg or DNA alone. One group received 8 microCi of radioactivity and were sacrificed at 5 and 20 min, and 1, 2, 4 and 24 h post-dose (n = 4/time point). A second group received the equivalent of 3.9 microCi of radioactivity and were sacrificed at 20 min, and 2 and 24 h for subsequent whole body autoradiographic analysis (WBA; n = 2/time point). The tissue distribution of intact DNA was assessed by Southern blot at 24 h post-dose, whereas the integrity of complexes and DNA incubated in heparinized whole blood was studied separately. In further studies, the time course of expression in lung tissue over a 48-h period was examined, and the relative lung-expression of purified open circular (OC) versus supercoiled (SC) DNA at 24 h was evaluated. Approximately 42% of the radioactivity was found in the lungs 5 min after injection and about half this percentage was found in the liver. By 2 h, only 5% remained in the lungs, but 48% was present in the liver. No other tissue accumulated >5% of the dose throughout the duration of the study. WBA radiograms confirmed the tissue distribution results and highlighted significant accumulation of radioactivity in bone over time. Southern Blot analysis demonstrated intact DNA in many tissues 24 h after dosing. In contrast, the majority of DNA incubated in blood was degraded within 2 h, although the complexes afforded some protection relative to DNA alone. The OC DNA expressed equivalently to SC DNA in lung tissue (OC = 1035 +/- 183 pg; SC = 856 +/- 257 pg/mg soluble protein, n = 6, mean +/- SEM) at 24 h, and detectable levels of CAT were present within 2 h of dosing (21.3 +/- 7.2 pg, n >/= 8, mean +/- SD). The results confirm that DNA-DOTIM:cholesterol complexes are initially deposited in the lungs after iv administration.     

Inhibitory effect of low molecular weight heparin on the bronchoconstriction in ovalbumin-sensitized guinea pigs after antigen exposure

To elucidate the effect of low molecular weight heparin (LMWH) on the bronchoconstriction, we examined the serial changes of the resistance of respiratory system (Rrs) in ovalbumin (OA)-sensitized guinea pigs after antigen exposure. After sensitization of guinea pigs with repeated OA inhalation, Rrs was measured at immediate asthmatic response (IAR) and late asthmatic response (LAR) with or without LMWH inhalation. Alteration in the number of inflammatory cells of the lung by LMWH inhalation was examined in the broncholaveolar lavage fluid (BALF) and in the histological sections of airway walls. Peak Rrs at 1 min up to 9 min, except 8 min, after antigen exposure significantly decreased by the pretreatment with LMWH inhalation as compared with saline inhalation. Peak Rrs at LAR (after 4 hours up to 24 hours, except 6 hours) also showed a significant decrease in the pretreatment with LMWH inhalation. Pretreatment of LMWH exhibited a decrease of eosinophil percentage in BALF (5.5 +/- 1.2% from 8.2 +/- 0.4% in saline inhalation) and a decrease of infiltrated eosinophil count in airway walls (71.0 +/- 7.3 from 155 +/- 15.8 in saline inhalation). These data show LMWH might play an important role as an inhibitory factor to bronchial asthma.     

The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes

STUDY OBJECTIVES: To determine the efficacy of the lung as an alternative route of delivery for insulin in controlling glucose below diabetic levels (11.2 mmol/L) 2 h after the ingestion of a meal in patients with type 2 diabetes mellitus. DESIGN: Single-blinded, nonrandomized, placebo-controlled pilot study consisting of two visits. SETTING: A primary care facility. PATIENTS: Seven patients with type 2 diabetes mellitus. INTERVENTIONS: On the first study visit, fasting glucose levels were normalized. Then, patients inhaled 1.5 U/kg insulin by aerosol into the lungs 5 min before ingesting a test meal. On the second visit, patients inhaled placebo aerosol 5 min before ingesting the same meal. On both visits, plasma samples were collected and analyzed for glucose levels for 3 h during the postprandial state. MEASUREMENTS AND RESULTS: No one coughed after inhalation of insulin aerosol or demonstrated hypoglycemia. During the postprandial period, glucose levels were significantly lower at 20 min (5.12+/-1.08 mmol/L), 1 h (7.87+/-0.73 mmol/L), 2 h (8.05+/-1.24 mmol/L) and 3 h (7.50+/-1.43 mmol/L) following inhalation of insulin than when the placebo was used. Data for the placebo were 10.36+/-1.23 mmol/L at 20 min, 14.0+/-1.68 mmol/L at 1 h, 16.18+/-1.45 mmol/L at 2 h, and 14.37+/-2.11 mmol/L at 3h (for all comparisons, p < 0.05). On the insulin visit, glucose levels were < 11.2 mmol/L 2 h after the meal in six of seven patients. None attained this level at the placebo visit. In addition, glucose levels were within the normal postprandial range of < 7.84 mmol/L in four of seven patients 2 h after eating on the insulin visit. CONCLUSIONS: These results suggest that, once plasma glucose levels are normalized, postprandial glucose levels can be maintained below diabetic levels by delivering 1.5 U/kg insulin into the lungs 5 min before the ingestion of a meal.     

Pulmonary carcinogenicity of relatively low doses of beta-particle radiation from inhaled 144CeO2 in rats

This study was conducted to examine the carcinogenic effects of inhaled beta-particle-emitting radionuclides, particularly in lower dose regions in which there were substantial uncertainties associated with available information. A total of 2751 F344/N rats (1358 males and 1393 females) approximately 12 weeks of age at exposure were used. Of these, 1059 rats were exposed to aerosols of 144CeO2 to achieve mean desired initial lung burdens (ILBs) of 18 kBq (low level), 247 rats to achieve mean ILBs of 60 kBq (medium level) and 381 rats to achieve mean ILBs of 180 kBq (high level). Control rats (total of 1064) were exposed to aerosols of stable CeO2. Based on the 95% confidence intervals of the median survival times and the cumulative survival curves, there were no significant differences in the survival of groups of female and male exposed rats relative to controls. The mean lifetime beta-particle doses to the lungs of the rats in the four groups were: low level, 3.6 +/- 1.3 (+/-SD) Gy; medium level, 12 +/- 4.5 Gy; and high level, 37 +/- 5.9 Gy. The crude incidence of lung neoplasms increased linearly with increasing doses to the lungs (controls, 0.57%; low level, 2.0%; medium level, 6.1%; and high level, 19%). The estimated linear risk coefficients for lung neoplasms per unit of dose to the lung were not significantly different for the three dose levels studied. The risk coefficient at the lower level was 39 +/- 14 (+/-SE) excess lung neoplasms per 10(4) rat Gy; at the medium level the risk was 47 +/- 12; and at the higher level the risk was 50 +/- 9.0. The relationship of beta-particle dose to the lung and the crude incidence of lung neoplasms was described adequately by a linear function. We concluded that the risk of lung neoplasms in rats per unit of radiation dose did not increase with decreasing mean beta-particle dose to the lung over the range of 3.6 to 37 Gy. The weighted average of these three values was 47 +/- 6.4 (+/-SE) excess lung neoplasms per 10(4) rat Gy. To extend the risk coefficients for lung neoplasms to lower doses by experimentation will require much larger numbers of rats than used in this study.     

Cardiovascular stimulation induced by rapid increases in desflurane concentration in humans results from activation of tracheopulmonary and systemic receptors

BACKGROUND: It was hypothesized that stimulation of rapidly adapting airway receptors produces the transient (2-4 min) circulatory responses to rapid increases in desflurane concentrations greater than 6%. Accordingly, it was reasoned that increasing the concentration of desflurane in one lung, without altering the concentration of desflurane in systemic blood, should cause cardiovascular stimulation, whereas once the airway receptors had adapted to the stimulation, an initial increase in the systemic concentration of desflurane should have little effect. METHODS: After placement of a double-lumen endotracheal tube in four volunteers and establishment of a steady-state level of 4% desflurane in both lungs, the desflurane concentration was rapidly increased from 4% to 8% in one lung while decreasing it in the other, thereby obviating any increase in the systemic desflurane blood concentration (confirmed by analysis). After returning the desflurane end-tidal concentration to 4% in both lungs, this process was repeated for the contralateral lung thereby having exposed both lungs to 8% desflurane without increasing the systemic desflurane concentration. After returning desflurane concentration to 4%, it was increased in both lungs simultaneously to 8% and consequently in blood to 8% of an atm. RESULTS: Rapid increases in desflurane concentrations in either lung, but not blood, significantly increased heart rate (17 +/- 5 beats/min, mean +/- SE, P < 0.05) and mean arterial blood pressure (15 +/- 5 mmHg, P < 0.05), but a greater increase in heart rate (43 +/- 5 beats/min, P < 0.05) and mean arterial blood pressure (46 +/- 11 mmHg, P < 0.05) occurred when both lungs were exposed simultaneously to rapidly increased desflurane concentration for the second time within 90 min. This result did not differ from the increase occurring on another day when both lungs and blood were exposed for the first time that day to 8% desflurane (heart rate 40 +/- 7 beats/min, P = 0.8; mean arterial blood pressure 40 +/- 3 mmHg, P = 0.5). CONCLUSIONS: It was concluded that at least two sites respond to a rapid increase in desflurane concentrations greater than 6%: one site in the airways and/or lungs, and at least one other in a highly perfused tissue(s). The systemic site contributes more importantly.